Patients with adult GH deficiency should receive GH replacement – Debate

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Development and Internal Validation of a Predictive Model for Adult GH Deficiency Prior to Stimulation Tests

BackgroundThe diagnosis of adult GH deficiency (GHD) relies on a reduced GH response to provocative tests. Their diagnostic accuracy, however, is not perfect, and a reliable estimation of pre-test GHD probability could be helpful for a better interpretation of their results.MethodsEighty patients showing concordant GH response to two provocative tests, i.e. the insulin tolerance test and the GHRH + arginine test, were enrolled. Data on IGF-I values and on the presence/absence of other pituitary deficits were collected and integrated for the estimation of GHD probability prior to stimulation tests.ResultsAn independent statistically significant association with the diagnosis of GHD was found both for IGF-I SDS (OR 0.34, 95%-CI 0.18-0.65, p=0.001) and for the presence of other pituitary deficits (OR 6.55, 95%-CI 2.06-20.83, p=0.001). A low (<25%) pre-test GHD probability could be predicted when IGF-I SDS > +0.91 in the presence of other pituitary deficits or IGF-I SDS > -0.52 in the absence of other pituitary deficits. A high (>75%) pre-test GHD probability could be predicted when IGF-I SDS < -0.82 in the presence of other pituitary deficits or IGF-I SDS < -2.26 in the absence of other pituitary deficits.ConclusionThis is the first study that proposes a quantitative estimation of GHD probability prior to stimulation tests. Our risk class stratification represents a simple tool that could be adopted for a Bayesian interpretation of stimulation test results, selecting patients who may benefit from a second stimulation test and possibly reducing the risk of wrong GHD diagnosis.

A Case With Adult GH Deficiency Complicated With Osteogenesis Imperfecta: Effect of GH Replacement on Bone Mineral Density

Background: Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. Bisphosphonates are the mainstay of pharmacologic fracture prevention therapy, although they aren’t officially approved for the treatment of OI. Clinical Case: The patient was born by breech delivery. After he had multiple fractures at the age of two years, he was diagnosed with osteogenesis imperfecta (OI) type I by genetic analysis (c.1299 + 1G> A mutation in the COL1A1 gene). On the growth curve, his height fell below -2SD at the age of six years. When he was 12 years old, he visited another hospital because of short stature (Hight 119 cm: -2.7SD). Pituitary MRI revealed pituitary stalk disruption and pituitary atrophy. Endocrinological examinations (ITT, TRH, LHRH, arginine stimulation tests) showed severe GH deficiency. Growth hormone replacement therapy was started. At the age of 16 years, he was diagnosed to have central hypothyroidism and central diabetes insipidus, and levothyroxine and DDAVP were started. His bone mineral density of the lumbar spine was 0.546 g/cm2, and alendronate was started. At the age of 17, central hypogonadism was diagnosed by LHRH stimulation test, and HCG injections were initiated. His bone mineral density continued to increase by GH replacement, HCG injections and bisphosphonate and reached 0.820 g/cm2 (Z-score: -0.27) by the age of 18 years. GH replacement was discontinued (final height 180 cm). At that age, his bone mineral density declined to 0.717 g/cm2 at the age of 25 years, although he stayed on an alendronate and HCG injections. At that time, total testosterone 890 ng/dL (142<n<923 ng/dL) was within normal range, but IGF-1 level was below the lower limit (44 ng/mL; -4.6SD, 225<n<337 ng/mL). He was referred to our hospital for transition to adult endocrine care. Endocrinologic evaluation revealed low serum cortisol level in the early morning (2.26 µg/dL, 7.07<n<19.6 μg/dL). GH-releasing peptide-2 stimulation test revealed severe GH deficiency (peak GH 0.18 ng/mL, n> 15 ng/mL (1)) and replacements with GH and hydrocortisone were initiated. After the GH replacement, the bone mineral density started to increase to 0.954 g/cm2 (Z-score: -0.5). Conclusion: So far as we know, this is the first case report of OI with panhypopituitarism treated with GH and bisphosphonate. This case suggests that bisphosphonate alone is not sufficient to maintain bone mineral density complicated with both OI and severe GHD. GH replacement therapy was inevitable to increase bone mineral density in this patient. Reference: (1) Kazuo Chihara et al. A simple diagnostic test using GH-releasing peptide-2 in adult GH deficiency. Eur J Endocrinol.2007;157;19-27.

From JMV-1843 to Macrilen

Growth hormone deficiency (GHD) is a severe pathology that greatly affects the quality of life, and increases morbidity and mortality of patients owing to the augmentation of cardiovascular events. Treatment of GHD is challenging, mainly because there is no specific characteristic sign or symptom that can be used to make a clear diagnosis. There is need for an unequivocal diagnosis of GHD to avoid unnecessary treatment with GH, because the available provocative tests (GH stimulation tests) are not specific and sensitive enough, and are contraindicated in some patients. Ghrelin is an endogenous peptide that stimulates GH secretion by interacting with a G-protein-coupled receptor named ghrelin receptor (GH secretagogue receptor 1a, GHS-R1a). Given this, a GH stimulation test using ghrelin or its analogues appears to be attractive. In this paper, a modified tripeptide first named JMV-1843 in the laboratory is briefly presented. It is potent and selective in stimulating the release of GH and is orally active. It has been recently commercialised for the diagnosis of adult GH deficiency under the tradename Macrilen. The test using this compound appears to be reliable, well tolerated, and simple.